Marked progress in the treatment of patients with advanced stage melanoma has occurred over the past two years. Along with vemurafenib, a targeted BRAF inhibitor, ipilimumab was recently approved for use in patients with metastatic disease. Ipilimumab therapy has potential to provide benefit to all melanoma patients because it acts systemically on the innate immune system via anti-CTLA-4 activity. Although ipilumimab therapy has shown a survival benefit, only a minority of patients derives durable responses, and an equivalent proportion of patients develop significant immune related adverse events (irAEs). In order to maximize the clinical utility of ipilimumab, it is critically important to identify potential biomarkers capable of delineating patients most likely to respond to therapy and those at increased risk for developing irAEs. However, no such biomarkers currently exist. Multiple lines of evidence suggest that inherited genetic variation may play a role in response to immunotherapies, such as ipilimumab, but also in the development of irAEs. Our preliminary data from a small genome-wide association (GWA) study examining outcomes related to ipilimumab therapy provide additional strong supportive evidence. To address our hypothesis that inherited variation is a determinant of both response and irAEs, we have identified patients treated on ipilimumab clinical trials from 10 academic contributing sites, two ECOG clinical trials and Bristol-Myers Squibb for a total of 716 and 1035 patients treated with 3mg/kg and 10mg/kg, respectively. We propose to determine the association of inherited variation with 1) irAEs and 2) overall survival at 1 and 2 years. In Aims 1 and 2, we will perform candidate-based gene and pathway analyses of genes involved in lymphocyte activation, cytokines, cytokine receptors and within the MHC region, as well as an agnostic genome-wide SNP-based approach to discover novel genetic markers associated with our outcomes of interest. In Aim 3, we will replicate our findings in an independent sample set. Our long term goal is to identify inherited variation that can inform clinical decision making for patients treated with ipilimumab. Of note, our results may have implications for other immunomodulatory immunotherapies and for other cancer types in which ipilimumab currently is being studied.